Acute inhibition of the Na+/Ca2+ exchanger reduces proarrhythmia in an experimental model of chronic heart failure.

Milberg P, Pott C, Frommeyer G, Fink M, Ruhe M, Matsuda T, Baba A, Klocke R, Quang TH, Nikol S, Stypmann J, Osada N, Müller FU, Breithardt G, Noble D, Eckardt L

Abstract

BACKGROUND: Molecular remodelling in heart failure includes slowing of repolarization, leading to proarrhythmia. OBJECTIVE: To evaluate the effects of NCX inhibition on repolarization as a novel antiarrhythmic concept in chronic heart failure (CHF). METHODS AND RESULTS: CHF was induced by rapid ventricular pacing in rabbits. LV function was assessed by echocardiography. Monophasic ventricular action potentials (MAP) showed a prolongation of repolarization in CHF after AV-block and stimulation at different cycle lengths. Sotalol (S; n=13, 100μM) or veratridine (V; n=15, 0.5μM) resulted in a further significant increase of MAP duration. CHF was associated with an increased dispersion of repolarization, as compared with S-(+22±7ms; p<0.05) and V-treated (+20±6ms; p<0.05) sham hearts. In the presence of a low potassium concentration, S and V reproducibly induced early afterdepolarizations (EAD) and polymorphic ventricular tachyarrhythmias (VT). SEA0400 (1μM), a pharmacological inhibitor of NCX, significantly shortened MAP duration (p<0.01) and reduced dispersion (p<0.05). It suppressed EAD in 6 of 13 S-CHF and in 9 of 10 V-CHF hearts, leading to a reduction of VT (60% in S-CHF; 83% in V-CHF hearts). Simulations using a mathematical model showed a reduction in action potential duration and number of EAD by NCX block in all subgroups. CONCLUSION: In an experimental model of chronic heart failure acute inhibition of NCX 1) reduces MAP duration 2) decreases dispersion of repolarization and 3) suppresses EAD and VT. Our observations indicate for the first time that pharmacological NCX inhibition increases repolarization reserve and protects against ventricular tachyarrhythmias in heart failure.